scholarly journals NK Cell Reconstitution in Paediatric Leukemic Patients after T-Cell-Depleted HLA-Haploidentical Haematopoietic Stem Cell Transplantation Followed by the Reinfusion of iCasp9-Modified Donor T Cells

2019 ◽  
Vol 8 (11) ◽  
pp. 1904 ◽  
Author(s):  
Helena Stabile ◽  
Paolo Nisti ◽  
Cinzia Fionda ◽  
Daria Pagliara ◽  
Stefania Gaspari ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Nk Cell ◽  
Haematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Donor T Cells

T-cell-depleted (TCD) human leukocyte antigen (HLA) haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) (TCD-haplo-HSCT) has had a huge impact on the treatment of many haematological diseases. The adoptive transfer of a titrated number of T cells genetically modified with a gene suicide can improve immune reconstitution and represents an interesting strategy to enhance the success of haplo-HSCT. Natural killer (NK) cells are the first donor-derived lymphocyte population to reconstitute following transplantation, and play a pivotal role in mediating graft-versus-leukaemia (GvL). We recently described a CD56lowCD16low NK cell subset that mediates both cytotoxic activity and cytokine production. Given the multifunctional properties of this subset, we studied its functional recovery in a cohort of children given α/βT-cell-depleted haplo-HSCT followed by the infusion of a titrated number of iCasp-9-modified T cells (iCasp-9 HSCT). The data obtained indicate that multifunctional CD56lowCD16low NK cell frequency is similar to that of healthy donors (HD) at all time points analysed, showing enrichment in the bone marrow (BM). Interestingly, with regard to functional acquisition, we identified two groups of patients, namely those whose NK cells did (responder) or did not (non responder) degranulate or produce cytokines. Moreover, in patients analysed for both functions, we observed that the acquisition of degranulation capacity was not associated with the ability to produce interferon-gamma (IFN-γ Intriguingly, we found a higher BM and peripheral blood (PB) frequency of iCas9 donor T cells only in patients characterized by the ability of CD56lowCD16low NK cells to degranulate. Collectively, these findings suggest that donor iCasp9-T lymphocytes do not have a significant influence on NK cell reconstitution, even if they may positively affect the acquisition of target-induced degranulation of CD56lowCD16low NK cells in the T-cell-depleted haplo-HSC transplanted patients.

scholarly journals NK cells expressing inhibitory KIR for non–self-ligands remain tolerant in HLA-matched sibling stem cell transplantation

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2686-2694 ◽  
Author(s):  
Andreas T. Björklund ◽  
Marie Schaffer ◽  
Cyril Fauriat ◽  
Olle Ringdén ◽  
Mats Remberger ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Nk Cell ◽  
Hla Class I ◽  
Class I ◽  
Hematopoietic Stem ◽  
Matched Sibling

Abstract Natural killer (NK)–cell alloreactivity in recipients of hematopoietic stem cell grafts from HLA-identical siblings is intriguing and has suggested breaking of NK-cell tolerance during the posttransplantation period. To examine this possibility, we analyzed clinical outcomes in a cohort of 105 patients with myeloid malignancies who received T cell–replete grafts from HLA-matched sibling donors. Presence of inhibitory killer cell immunoglobulin-like receptors (KIRs) for nonself HLA class I ligands had no effect on disease-free survival, incidence of relapse, or graft-versus-host disease. A longitudinal analysis of the NK-cell repertoire and function revealed a global hyporesponsiveness of NK cells early after transplantation. Functional responses recovered at approximately 6 months after transplantation. Importantly, NKG2A− NK cells expressing KIRs for nonself HLA class I ligands remained tolerant at all time points. Furthermore, a direct comparison of NK-cell reconstitution in T cell–replete and T cell–depleted HLA-matched sibling stem cell transplantation (SCT) revealed that NKG2A+ NK cells dominated the functional repertoire early after transplantation, with intact tolerance of NKG2A− NK cells expressing KIRs for nonself ligands in both settings. Our results provide evidence against the emergence of alloreactive NK cells in HLA-identical allogeneic SCT.

scholarly journals T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation

Blood ◽  
2012 ◽  
Vol 120 (9) ◽  
pp. 1820-1830 ◽  
Author(s):  
Luca Vago ◽  
Giacomo Oliveira ◽  
Attilio Bondanza ◽  
Maddalena Noviello ◽  
Corrado Soldati ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Suicide Gene ◽  
Hematopoietic Stem ◽  
Donor T Cells

Abstract The genetic modification of T cells with a suicide gene grants a mechanism of control of adverse reactions, allowing safe infusion after partially incompatible hematopoietic stem cell transplantation (HSCT). In the TK007 clinical trial, 22 adults with hematologic malignancies experienced a rapid and sustained immune recovery after T cell–depleted HSCT and serial infusions of purified donor T cells expressing the HSV thymidine kinase suicide gene (TK+ cells). After a first wave of circulating TK+ cells, the majority of T cells supporting long-term immune reconstitution did not carry the suicide gene and displayed high numbers of naive lymphocytes, suggesting the thymus-dependent development of T cells, occurring only upon TK+-cell engraftment. Accordingly, after the infusions, we documented an increase in circulating TCR excision circles and CD31+ recent thymic emigrants and a substantial expansion of the active thymic tissue as shown by chest tomography scans. Interestingly, a peak in the serum level of IL-7 was observed after each infusion of TK+ cells, anticipating the appearance of newly generated T cells. The results of the present study show that the infusion of genetically modified donor T cells after HSCT can drive the recovery of thymic activity in adults, leading to immune reconstitution.

scholarly journals RNA-seq of human T cells after hematopoietic stem cell transplantation identifies Linc00402 as a regulator of T cell alloimmunity

2021 ◽  
Vol 13 (585) ◽  
pp. eaaz0316
Author(s):  
Daniel Peltier ◽  
Molly Radosevich ◽  
Visweswaran Ravikumar ◽  
Sethuramasundaram Pitchiaya ◽  
Thomas Decoville ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Differential Expression ◽  
Cell Transplantation ◽  
Hematopoietic Stem ◽  
Human T Cells ◽  
Donor T Cells

Mechanisms governing allogeneic T cell responses after solid organ and allogeneic hematopoietic stem cell transplantation (HSCT) are incompletely understood. To identify lncRNAs that regulate human donor T cells after clinical HSCT, we performed RNA sequencing on T cells from healthy individuals and donor T cells from three different groups of HSCT recipients that differed in their degree of major histocompatibility complex (MHC) mismatch. We found that lncRNA differential expression was greatest in T cells after MHC-mismatched HSCT relative to T cells after either MHC-matched or autologous HSCT. Differential expression was validated in an independent patient cohort and in mixed lymphocyte reactions using ex vivo healthy human T cells. We identified Linc00402, an uncharacterized lncRNA, among the lncRNAs differentially expressed between the mismatched unrelated and matched unrelated donor T cells. We found that Linc00402 was conserved and exhibited an 88-fold increase in human T cells relative to all other samples in the FANTOM5 database. Linc00402 was also increased in donor T cells from patients who underwent allogeneic cardiac transplantation and in murine T cells. Linc00402 was reduced in patients who subsequently developed acute graft-versus-host disease. Linc00402 enhanced the activity of ERK1 and ERK2, increased FOS nuclear accumulation, and augmented expression of interleukin-2 and Egr-1 after T cell receptor engagement. Functionally, Linc00402 augmented the T cell proliferative response to an allogeneic stimulus but not to a nominal ovalbumin peptide antigen or polyclonal anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a regulator of allogeneic T cell function.

Clinical Correlation of Foxp3 Regulatory Gene Expressions and NK Cells in Early Engraftment after Myeloablative Allogeneic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2911-2911
Author(s):  
Deok-Hwan Yang ◽  
Chung-Sun Park ◽  
Yeo-Kyeoung Kim ◽  
Je-Jung Lee ◽  
Hyeoung Joon Kim
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Nk Cell ◽  
Gene Expressions ◽  
Foxp3 Gene

Abstract Regulatory T cells (Tregs) have been established as a key role of self tolerance and preventing proliferation of auto- and alloantigen-reactive T cells. CD4+CD25+ Tregs suppress GVHD in animal models, but in human data on GVHD following stem cell transplantation (SCT) is conflicting. We postulate that CD4+Foxp3+Tregs not only reduce the incidence of acute graft-versus host disease (aGVHD) but inhibit the NK cell functions in patients who received allogeneic SCT. CD4+Foxp3+Tregs also may adversely affect the GVL effect and cause the relapse of disease. Patients and Methods: 25 patients (AML:13, ALL:9, CML:2, NHL:1) were undergone allogeneic SCT. Nine patients were infused from unrelated donor and five patients were from HLA one-mismatch. Three patients added alemtuzumab to myeloablative conditioning regimen due to HLA mismatch. Peripheral blood mononuclear cell (PBMC) were separated 3 or 4 weeks after SCT when absolute neutrophil count reached above 1000 × 109/L. NK cells were phenotypically analyzed by flow cytometry using directly conjugated antibodies to CD3 and CD56. CD4+ cells were isolated from PBMC using micro-bead (MACS) and the expression levels of Foxp3 mRNA were assessed by quantitative real-time PCR. Results: 12 patients developed grade 2–4 acute GVHD and 10 patients relapsed. Patients who experienced Gr2-4 aGVHD had significantly lower the relapse rate than those who Gr0-1 aGVHD (P=0.002). Foxp3 gene expressions within CD4+ T cells were significantly lower in Gr2-4 aGVHD patients (median, 4.278 ng/μl) than in Gr0-1 aGVHD patients (median 7.914 ng/μl) except three patients treated with alemtuzumab conditioning (P=0.016). All of three patients used alemtuzumab experienced the relapse and no aGVHD. They also had very lower Foxp3 gene expressions (median, 4.760 ng/μl) than those in Gr0-1 aGVHD patients. Without alemtuzumab used patients, the levels of Foxp3 expression in relapsed patients were significantly higher than those in non-relapsed patients (median, 11.684 ng/μl and 2.031 ng/μl, respectively) (P=0.001). However, we could not find an inverse correlation between NK cell expressions and CD4+Foxp3+Tregs and a positive correlation between infused T cell doses and CD4+Foxp3+Tregs expression. Conclusion: The levels of CD4+Foxp3+Tregs affect the incidence of aGVHD and predict the risk of the relapse. Alemtuzumab may influence the T cell recovery including regulatory T cells after early post-SCT.

scholarly journals Human NK Cells in Autologous Hematopoietic Stem Cell Transplantation for Cancer Treatment

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1589
Author(s):  
Ane Orrantia ◽  
Iñigo Terrén ◽  
Gabirel Astarloa-Pando ◽  
Olatz Zenarruzabeitia ◽  
Francisco Borrego
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cell Biology ◽  
Nk Cell ◽  
Hematopoietic Stem ◽  
Autologous Hsct

Natural killer (NK) cells are phenotypically and functionally diverse lymphocytes with the ability to recognize and kill malignant cells without prior sensitization, and therefore, they have a relevant role in tumor immunosurveillance. NK cells constitute the main lymphocyte subset in peripheral blood in the first week after hematopoietic stem cell transplantation (HSCT). Although the role that NK cells play in allogenic HSCT settings has been documented for years, their significance and beneficial effects associated with the outcome after autologous HSCT are less recognized. In this review, we have summarized fundamental aspects of NK cell biology, such as, NK cell subset diversity, their effector functions, and differentiation. Moreover, we have reviewed the factors that affect autologous HSCT outcome, with particular attention to the role played by NK cells and their receptor repertoire in this regard.

scholarly journals Mouse Models of Antigen Presentation in Hematopoietic Stem Cell Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Motoko Koyama ◽  
Geoffrey R. Hill
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Mouse Models ◽  
Major Complication ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Donor T Cells ◽  
Immune Pathology

Allogeneic stem cell transplantation (alloSCT) is a curative therapy for hematopoietic malignancies. The therapeutic effect relies on donor T cells and NK cells to recognize and eliminate malignant cells, known as the graft-versus-leukemia (GVL) effect. However, off target immune pathology, known as graft-versus-host disease (GVHD) remains a major complication of alloSCT that limits the broad application of this therapy. The presentation of recipient-origin alloantigen to donor T cells is the primary process initiating GVHD and GVL. Therefore, the understanding of spatial and temporal characteristics of alloantigen presentation is pivotal to attempts to separate beneficial GVL effects from detrimental GVHD. In this review, we discuss mouse models and the tools therein, that permit the quantification of alloantigen presentation after alloSCT.

scholarly journals Donor and host coexpressing KIR ligands promote NK education after allogeneic hematopoietic stem cell transplantation

2019 ◽  
Vol 3 (24) ◽  
pp. 4312-4325 ◽  
Author(s):  
Xiang-Yu Zhao ◽  
Xing-Xing Yu ◽  
Zheng-Li Xu ◽  
Xun-Hong Cao ◽  
Ming-Rui Huo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Nk Cell ◽  
K562 Cells ◽  
Inhibitory Receptors ◽  
Hematopoietic Stem

Abstract The rate and extent of natural killer (NK)–cell education after hematopoietic cell transplantation correlates with leukemia control. To study the effect of donor and host HLA on NK-cell reconstitution, single killer-cell immunoglobulin-like receptor (KIR)+ NK cells (exhibiting KIR2DL1, KIR2DL2/KIR2DL3, or KIR3DL1 as their sole receptor) were grouped into 4 groups based on the interaction between donor/host HLA and donor inhibitory KIR in 2 cohorts (n = 114 and n = 276, respectively). On days 90 to 180 after transplantation, the absolute number and responsiveness against K562 cells (CD107a or interferon-γ expression) of single-KIR+ NK cells were higher in pairs where donor and host HLA both expressed ligands for donor inhibitory KIRs than in pairs where 1 or both of the donor and recipient HLA lacked at least 1 KIR ligand. NK-cell responsiveness was tuned commensurate with the number of inhibitory receptors from the donor. When both donor and host expressed the 3 major KIR ligands (HLA-C1, HLA-C2, and HLA-Bw4), NK cells expressing 3 inhibitory receptors (KIR2DL1/2DL3/3DL1) reached the maximum responsiveness against K562 cells compared with those NK cells expressing only 1 or 2 inhibitory receptors. When donor and host HLA both expressed all ligands for donor inhibitory KIRs, patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) showed the lowest recurrence rate after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). In conclusion, this study demonstrates that when both donors and hosts present all the KIR ligands for donor KIRs, reconstituted NK cells achieve better functional education and contribute to least relapse among patients. This observation study was registered at www.clinicaltrials.gov as #NCT02978274.

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